Animal studies have established the importance of the hypothalamus in the control of appetite and energy expenditure. Nuclei within this area of the brain integrate inputs from adipose tissue reflecting body fat stores and the gastrointestinal tract reflecting the amount and types of food ingested. These afferent signals trigger changes in food intake and energy expenditure through mechanisms involving both immediate alterations in neuronal cell electrical activity and relatively slower effects mediated via hormone-receptor binding. While these concepts of a central integrative center controlling weight regulation are well studied in animal models, the importance of these findings to humans is less clear. This is in large part due to a lack of tools available to study neuronal responses to various effectors in-vivo in humans. Functional nuclear magnetic imaging (fMRI) is a non-invasive, non-radioactive imaging technique that detects real-time changes in neuronal electrical activity to within a few millimeters in the brain. fMRI has been used to study the brain's response to ingestion of glucose and shown differences in this response between lean and obese subjects. However, questions remain regarding the specificity of these differences for nutrients (as opposed to gut hormones) and interactions of different macronutrients with central centers involved in weight regulation in humans. The proposals in this pilot grant will bring together investigators with backgrounds in clinical research, basic electrophysiological and neuroendocrine mechanisms of obesity, and fMRI imaging to better understand how nutrients affect brain activity in hypothalamic and brainstem regions involved with weight regulation in humans. The first aim will use fMRI to determine hypothalamic and brainstem responses to intravenous glucose and fructose in lean and obese subjects. The second aim will determine if lipids affect central glucose responsiveness as suggested by weight gain on high-fat diets in rodent models. Experience and data gained from these studies will be used in future proposals of effects on brain activity to mixed meals, long-term feeding of diets of differing macronutrient content, as well as to infusions of individual and combinations of gut-derived hormones secreted in response to meals and adipocyte hormones such as leptin. Simultaneous sampling of blood for levels of nutrients, insulin, leptin, and other hormones involved in weight regulation will give insight into the role they may play in changes in fMRI signaling in weight regulation centers in the brain. Lay Description: This study will use functional MRI scanning to explore how the brain is affected by sugar and fat. These studies will help us to better understand why changes in the diet might lead to weight gain or loss. [unreadable] [unreadable] [unreadable]